The microbiomes of humans and other animals are complex and poorly understood, but there is growing appreciation that they affect health in a wide variety of ways. Most potential invading pathogens interact extensively with a complex ecosystem of resident microbes before they can even contact host tissues. These interactions are clearly important, but have been very difficult to study for lack of tractable experimental systems. Our innovative recent work has established an experimental system in which the resident microbiome can protect against invasion by some species of bordetellae but not others that are very closely related. We further made the complementary finding that other bordetellae can displace the resident microbiota from the respiratory tract, including long-term chronic colonizers. Our extensive experience with the comparative biology and genomics of these closely related species has revealed candidate genes involved and our reverse genetics has allowed us to begin to identify roles for some of these, as described in our preliminary results. These data are beginning to reveal the complex interactions with resident microbiota as a critical aspect of an invading pathogen's initial colonization of the mammalian respiratory tract. This proposal will determine the ecological mechanisms involved in this competition, and identify molecular mechanisms (genes), in the context of naturally occurring interactions with resident microbiota that determine susceptibility/resistance to invading pathogens.